Progressive fibrosis of liver often results in organ failure leading to death or the need for transplantation. These diseases affect hundreds of millions in the United States and worldwide [1]. For example, hepatic fibrosis is the leading non-malignant gastrointestinal cause of death in the United States. Moreover, it has been increasingly recognized that progression of fibrosis is the single most important determinant of morbidity and mortality in patients with chronic liver disease [2].
There has been remarkable progress in elucidating the cellular basis of fibrosis in liver, kidney and lung. In liver, activation of resident mesenchymal cells known as “stellate cells” is a key event [3]. Activation represents a transformation to a myofibroblast-like cell that is proliferative, fibrogenic and contractile. The extent of fibrosis is directly related to the numbers of these fibrogenic activated stellate cells.
It has been previously demonstrated that activation and proliferation of hepatic stellate cells (HSC) in liver injury is associated with de novo expression of many cytokine receptors, including beta platelet-derived growth factor receptor (β-PDGFR) [4]. β-PDGF receptor expression in injured liver is largely confined to these activated mesenchymal cells; the rare large arteries within the parenchyma are the only other site within the organ. Thus, the extent of β-PDGF receptor expression parallels the mass of activated stellate cells, which in turn reflects the extent of fibrosis. Moreover, reduction in fibrosis is accompanied by diminished numbers of such activated cells [5].
Recent advances in anti-inflammatory arid-anti-fibrotic therapies offers the prospect of delaying these outcomes, but to date there are no approved antifibrotic therapies, leaving hundreds of millions of patients worldwide who have chronic liver disease with no therapeutic options apart from the possibility of liver transplantation. Currently only a single trial of antifibrotic therapy is underway (gamma interferon), and the hepatology community and pharmaceutical sector anxiously await results from this trial, as several other putative antifibrotics agents are in development by a number of companies. There has been growing recognition and enthusiasm for the prospect of treating hepatic fibrosis [6]. Thus, there is a large untapped market that is highly receptive to this new approach to treating liver fibrosis.
The development of imatinib mesylate (GLEEVEC™) represented an important milestone in the treatment of chronic myelogenous leukemia (CML), since this small molecular inhibitor of the BCR-ABL oncogene product, the key molecular abnormality in this cancer, is remarkably safe and effective [7–9]. The drug is also effective in CML associated with rearrangements of the β-PDGF receptor [10]. Thus, thousands of patients have been safely treated with modest drug resistance reported. More recently, the drug has been approved for the treatment of GI Stromal tumors, mesenchymal cell neoplasms of the intestinal tract [11]. Of importance, this agent not only blocks the BCR-ABL receptor tyrosine kinase protein, but it has inhibitory activity across a number of related receptor tyrosine kinases, including β-PDGF receptor, a key mediator of stellate cell activation in hepatic fibrosis[12]. Indeed, a recent report has begun to examine the potential impact of GLEEVEC™ on hepatic fibrosis in a rodent model of bile duct obstruction, a standard model used in the field[13].